[Frontiers in Bioscience, Scholar, 11, 75-88, March 1, 2019] The persisting puzzle of racial disparity in triple negative breast cancer: looking through a new lens Chakravarthy Garlapati1, Shriya Joshi1, Bikram Sahoo1, Shobhna Kapoor2, Ritu Aneja1 1Department of Biology, Georgia State University, Atlanta, GA, USA, 2Department of Chemistry, Indian Institute of Technology Bombay, Powai, India TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Dissecting the TNBC racially disparate burden 3.1. Does race influence TNBC onset and progression? 3.2. Tumor microenvironment in TNBC and racial disparity 3.3. Differential gene signatures and pathways in racially distinct TNBC 3.4. Our Perspective: Looking racial disparity through a new lens 4. Conclusion 5. Acknowledgement 6. References 1. ABSTRACT 2. INTRODUCTION Triple-negative breast cancer (TNBC) Triple-negative breast cancer (TNBC), is characterized by the absence of estrogen a subtype of breast cancer (BC), accounts for and progesterone receptors and absence 15-20% of all BC diagnoses in the US. It has of amplification of human epidermal growth been recognized that women of African descent factor receptor (HER2). This disease has no are twice as likely to develop TNBC than approved treatment with a poor prognosis women of European descent (1). As the name particularly in African-American (AA) as foretells, TNBCs lack estrogen, progesterone, compared to European-American (EA) and human epidermal growth factor receptors. patients. Gene ontology analysis showed Unfortunately, TNBCs are defined by what they specific gene pathways that are differentially “lack” rather than what they “have” and thus this regulated and gene signatures that are negative nomenclature provides no actionable differentially expressed in AA as compared to information on “druggable” targets. Aptly, this EA. Such differences might underlie the basis particular BC subtype has no FDA-approved for the aggressive nature and poor prognosis of targeted therapies thus far, and the survival TNBC in AA patients. In-depth studies of these rate is dismal (2-5). pathways and differential genetic signature might give significant clues to improve our Primarily, TNBC patients exhibit higher understanding of tumor biology associated resistance to chemotherapy than hormone with AA TNBC to advance the prognosis receptor (HR) positive BCs (6). TNBC patients, and survival rates. Along with gene ontology whose tumors metastasize to visceral organs, analysis, we suggest that post-translational survive only for a year. Thus, diagnosis of modifications (PTM) could also play a crucial metastatic TNBC is necessarily a death role in the dismal survival rate of AA TNBC sentence for patients (6). The heterogeneous patients. Further investigations are necessary tumor biology, aggressive clinical course, to explore this terrain of PTMs to identify the and higher metastatic potential underscore racially disparate burden in TNBC. an unmet need to understand the molecular 75 The unsolved puzzle of triple negative breast cancer racial disparity 3. DISSECTING THE TNBC RACIALLY DISPARATE BURDEN 3.1. Does race influence TNBC onset and progression? TNBC in AA women present higher mortality rates compared to women of European descent. The major contributing factors for such disparity are barriers to early screening, advanced disease stage at diagnosis, socio-demographic factors, socio- economic status, and lack of access to the healthcare treatment (17). AA premenopausal women exhibit a higher incidence and mortality rate compared to EA counterparts. However, postmenopausal women, do not show such a racial disparity (4, 18), suggesting that TNBC is significantly associated with younger age women of African descent (5). Figure 1. Variety of critical aspects attributed to TNBC aggressiveness. Differences in survival outcomes among racially diverse TNBC patients remains controversial. Studies led by various groups pathways and signaling circuitries that could such as Lund et al., (19) Bauer et al., (5) be targeted in TNBC to develop effective novel Carey et al., (20) and Sachdev et al., (21) molecules to ultimately improve its prognosis (7) have reported worse survival outcomes for (Figure 1). Literature reports several targeted women of African origin, after adjusting for molecular therapies for TNBC that have shown socioeconomic factors, treatment delay, and promising results. These novel agents include tumor characteristics. Sachdev et al., showed small molecule inhibitors that specifically target that both unadjusted and stage-adjusted poly-ADP-ribose-polymerase (PARP-1) (8, 9), survival outcomes were better in EA over epidermal growth factor receptor (EGFR) (10, 11), AA TNBC patients (21). On the other hand, multi-tyrosine kinases (12, 13), as well as anti- other groups like Dawood et al., (22) O’ Brien angiogenic agents (14, 15). A study by Sparano et al., (23) and Sparano et al., (24) found no JA et al., pointed out a distinct molecular significant difference in survival outcomes signature; ~70% of genes related to kinase between racially-distinct TNBC patients (4). activity, cell division, proliferation, DNA repair, Underlying these inconsistent results could be anti-apoptosis, and transcriptional regulation are the nonuniformity of the biomarkers tested, lack differentially expressed in TNBC vs. non-TNBC of certainty of pathological parameters, lack of subtype (16). This review focuses on racially- availability of treatment information to deduce distinct differential gene expression signatures the survival outcomes, and failure to consider in TNBC and how these distinct features may multiple factors such as stage, grade, poverty provide insights into the mechanistic basis index, and other treatment related factors (19). for aggressive TNBC and offer cues about druggable target space in racially diverse TNBC Recently, Ademuyiwa et al., reported a patients. More importantly, we offer a new detailed mutational analysis of AA and EA TNBC perspective to look at racial disparities through patients comparing the mutational landscape the lens of post-translational modifications of between the racially-distinct patient populations. key molecules. Interestingly, they found no compelling 76 © 1996-2019 The unsolved puzzle of triple negative breast cancer racial disparity differences in the panorama of mutated genes tumor microenvironment (TME) to enhance between AA and EA TNBC patients. Also, they the crosstalk with various other cells. Apart found no racial differences between AA and EA from tumor cells, TME is comprised of immune TNBC patients in high prevalence genes (TP53, cells, fibroblasts, lymphocytes, signaling PI3CA, MLL3), attributed to the fact that there molecules, and tumor vasculature proteins. is no significant difference in somatic mutations TME supports the growth, angiogenesis and of these genes (25). Collectively, these findings metastasis of tumor cells (54). It has been suggest that the aggressive disease course seen reported that TME significantly influences among AA TNBC patients may be independent the malignant behavior and is crucial for of the dysregulation in common tumor growth reprogramming the surrounding cells in TNBC. promoting pathways. It is likely that there may Myriad of available literature suggest that tumor be hitherto unknown biomarkers that offer an infiltrating lymphocytes (TILs) are critical in enhanced understanding of the racial divide in regulating TNBC microenvironment. Elevated TNBC outcomes. number of T regulatory cells (Tregs) in TME has been correlated with poor prognosis in many Studies above suggest that the TNBC types of cancers including TNB (55, 56). Our incidence and mortality rates are higher in unpublished data demonstrate a higher fraction AA compared to EA, even after adjusting for of TILs in AA over EA TNBCs, suggesting that clinical and socioeconomic variables that might TME plays an essential role in racially disparate explain the differential outcome among the TNBC population. Moreover, vast majority of races (17). Thus, it is tempting to speculate that literature shed light on various TME related intrinsic biological factors might be responsible molecules (CXCL12, CXCR4, VEGF, Resistin, for the racially disparate burden of TNBC. In MCP1, MMP2, MMP-9, SOS1, PSPHL, uPA, this lieu, it has been shown that TNBC patients IL6, RASSF1A, etc.) that are significantly of African descent harbor a higher prevalence up-regulated in AA over EA BC (57). These of the basal-like-1 tumor phenotype which is molecules along with their precise molecular characterized by enhanced proliferation and action warrants further investigations to sensitivity to chemotherapy (17). AA women delineate the aggressive tumor biology with TNBC tumors demonstrate a higher rate associated with AA TNBC. Previously, various of invasion, distant metastasis (7.37% vs. groups have reported that tougher extracellular 4.67%, p=0.05), angiogenesis and cell growth matrix (ECM) was efficient in blocking the compared to their EA counterparts (26). Thus, crosstalk between the cells. However, the proteins/biomarkers that are differentially recent data have suggested that stiffer the tumor expressed among the races and are involved stroma, more aggressive the breast cancer in pathways associated with cell cycle subtype is likely to be (55, 58). Thus, increased regulation, epithelial-mesenchymal transition ECM rigidity might contribute in altering the (EMT), and angiogenesis may hold the key mechano-signaling, tumor vasculature and pro- to